| Abstract No.: | A-D1155 |
| Country: | Canada |
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| Title: | MECHANISMS UNDERLYING INCREASE IN LEVELS AND EFFECTS OF ADRENOMEDULLIN IN MORPHINE TOLERANCE. |
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| Authors/Affiliations: | 1 Jean-Guy Chabot; 1 Jean-Guy Chabot*; 1 Yanguo Hong; 1 Yanguo Hong; 2 Alain Fournier; 1 Remi Quirion;
1 Douglas Mental Health University Institute, Montreal, QC,Canada; 2 INRS-Institut Armand-Frappier, Laval, QC, Canada
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| Content: | We have observed that up-regulation of adrenomedullin (AM), a member of the CGRP family, is involved in the development of morphine tolerance. The current study was designed to explore the underlining mechanism involved in the increase in AM during tolerance to morphine. Intrathecal administration of morphine (20 µg, daily) for 6 days induced increases in CGRP in small and medium dorsal root ganglia (DRG) neurons and CGRP content in the spinal dorsal horn. These responses were completely prevented when AM22-52 (10 nmol), an AM antagonist, was co-administered daily with morphine. In vitro study showed that culturing DRG explants from adult rat with morphine for 6 days at concentrations of 1, 3.3 and 10 µM (but not 100 µM) increased AM levels. These increases were attenuated in the presence of the protein kinase C inhibitor Gö-6976 (10, 100 and 1000 nM). The content of CGRP was increased following treatment with AM (0.1, 1, 10 and 100 nM) at 24 hours, but not at 2 and 6 hours. However, treatment with CGRP (1, 10 and 100 nM) for 24 hours did not alter the content of AM. Taken together, these data suggest that chronic morphine increased AM synthesis at the spinal level through the activation of protein kinase C, and that AM-evoked loss of morphine analgesia may be mediated by increase in CGRP levels. (Supported by the Canadian Institutes of Health Research) |
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